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  1. Moullaali TJ, Wang X, Woodhouse LJ, Law ZK, Delcourt C, Sprigg N, et al.
    BMJ Open, 2019 07 16;9(7):e030121.
    PMID: 31315876 DOI: 10.1136/bmjopen-2019-030121
    INTRODUCTION: Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH.

    METHODS AND ANALYSIS: A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics.

    ETHICS AND DISSEMINATION: No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals.

    PROSPERO REGISTRATION NUMBER: CRD42019141136.

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  2. Law ZK, Ali A, Krishnan K, Bischoff A, Appleton JP, Scutt P, et al.
    Stroke, 2020 01;51(1):121-128.
    PMID: 31735141 DOI: 10.1161/STROKEAHA.119.026128
    Background and Purpose- Blend, black hole, island signs, and hypodensities are reported to predict hematoma expansion in acute intracerebral hemorrhage. We explored the value of these noncontrast computed tomography signs in predicting hematoma expansion and functional outcome in our cohort of intracerebral hemorrhage. Methods- The TICH-2 (Tranexamic acid for IntraCerebral Hemorrhage-2) was a prospective randomized controlled trial exploring the efficacy and safety of tranexamic acid in acute intracerebral hemorrhage. Baseline and 24-hour computed tomography scans of trial participants were analyzed. Hematoma expansion was defined as an increase in hematoma volume of >33% or >6 mL on 24-hour computed tomography. Poor functional outcome was defined as modified Rankin Scale of 4 to 6 at day 90. Multivariable logistic regression was performed to identify predictors of hematoma expansion and poor functional outcome. Results- Of 2325 patients recruited, 2077 (89.3%) had valid baseline and 24-hour scans. Five hundred seventy patients (27.4%) had hematoma expansion while 1259 patients (54.6%) had poor functional outcome. The prevalence of noncontrast computed tomography signs was blend sign, 366 (16.1%); black hole sign, 414 (18.2%); island sign, 200 (8.8%); and hypodensities, 701 (30.2%). Blend sign (adjusted odds ratio [aOR] 1.53 [95% CI, 1.16-2.03]; P=0.003), black hole (aOR, 2.03 [1.34-3.08]; P=0.001), and hypodensities (aOR, 2.06 [1.48-2.89]; P<0.001) were independent predictors of hematoma expansion on multivariable analysis with adjustment for covariates. Black hole sign (aOR, 1.52 [1.10-2.11]; P=0.012), hypodensities (aOR, 1.37 [1.05-1.78]; P=0.019), and island sign (aOR, 2.59 [1.21-5.55]; P=0.014) were significant predictors of poor functional outcome. Tranexamic acid reduced the risk of hematoma expansion (aOR, 0.77 [0.63-0.94]; P=0.010), but there was no significant interaction between the presence of noncontrast computed tomography signs and benefit of tranexamic acid on hematoma expansion and functional outcome (P interaction all >0.05). Conclusions- Blend sign, black hole sign, and hypodensities predict hematoma expansion while black hole sign, hypodensities, and island signs predict poor functional outcome. Noncontrast computed tomography signs did not predict a better response to tranexamic acid. Clinical Trial Registration- URL: https://www.isrctn.com. Unique identifier: ISRCTN93732214.
    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  3. Dineen RA, Pszczolkowski S, Flaherty K, Law ZK, Morgan PS, Roberts I, et al.
    BMJ Open, 2018 02 03;8(2):e019930.
    PMID: 29431141 DOI: 10.1136/bmjopen-2017-019930
    OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses).

    DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214).

    SETTING: International multicentre hospital-based study.

    PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection.

    INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol.

    CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH.

    ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting.

    TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre-results.

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  4. Ovesen C, Jakobsen JC, Gluud C, Steiner T, Law Z, Flaherty K, et al.
    BMC Res Notes, 2018 Jun 13;11(1):379.
    PMID: 29895329 DOI: 10.1186/s13104-018-3481-8
    OBJECTIVE: We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants' spot sign status.

    RESULTS: Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients. Trial registration ISRCTN93732214 ( http://www.isrctn.com ).

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  5. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Lancet, 2018 05 26;391(10135):2107-2115.
    PMID: 29778325 DOI: 10.1016/S0140-6736(18)31033-X
    BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.

    METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.

    FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).

    INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

    FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  6. Flaherty K, Bath PM, Dineen R, Law Z, Scutt P, Pocock S, et al.
    Trials, 2017 Dec 20;18(1):607.
    PMID: 29262841 DOI: 10.1186/s13063-017-2341-5
    RATIONALE: Aside from blood pressure lowering, treatment options for intracerebral haemorrhage remain limited and a proportion of patients will undergo early haematoma expansion with resultant significant morbidity and mortality. Tranexamic acid (TXA), an anti-fibrinolytic drug, has been shown to significantly reduce mortality in patients, who are bleeding following trauma, when given rapidly. TICH-2 is testing whether TXA is effective at improving outcome in spontaneous intracerebral haemorrhage (SICH).

    METHODS AND DESIGN: TICH-2 is a pragmatic, phase III, prospective, double-blind, randomised placebo-controlled trial. Two thousand adult (aged ≥ 18 years) patients with an acute SICH, within 8 h of stroke onset, will be randomised to receive TXA or the placebo control. The primary outcome is ordinal shift of modified Rankin Scale score at day 90. Analyses will be performed using intention-to-treat.

    RESULTS: This paper and its attached appendices describe the statistical analysis plan (SAP) for the trial and were developed and published prior to database lock and unblinding to treatment allocation. The SAP includes details of analyses to be undertaken and unpopulated tables which will be reported in the primary and key secondary publications. The database will be locked in early 2018, ready for publication of the results later in the same year.

    DISCUSSION: The SAP details the analyses that will be done to avoid bias arising from prior knowledge of the study findings. The trial will determine whether TXA can improve outcome after SICH, which currently has no definitive therapy.

    TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN93732214 . Registered on 17 January 2013.

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
  7. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Health Technol Assess, 2019 07;23(35):1-48.
    PMID: 31322116 DOI: 10.3310/hta23350
    BACKGROUND: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage.

    OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH).

    DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial.

    SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK).

    PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset.

    EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy  4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.

    CONCLUSIONS: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.

    FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed.

    TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214.

    FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.

    Matched MeSH terms: Cerebral Hemorrhage/drug therapy*
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